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PAI-1–regulated extracellular proteolysis governs senescence and survival in Klotho mice
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PAI-1–regulated extracellular proteolysis governs senescence and survival in Klotho mice
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Journal Article
PAI-1–regulated extracellular proteolysis governs senescence and survival in Klotho mice
2014
Overview
Cellular senescence restricts the proliferative capacity of cells and is accompanied by the production of several proteins, collectively termed the “senescence-messaging secretome” (SMS). As senescent cells accumulate in tissue, local effects of the SMS have been hypothesized to disrupt tissue regenerative capacity. Klotho functions as an aging-suppressor gene, and Klotho -deficient (kl/kl) mice exhibit an accelerated aging-like phenotype that includes a truncated lifespan, arteriosclerosis, and emphysema. Because plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor (SERPIN), is elevated in kl/kl mice and is a critical determinant of replicative senescence in vitro, we hypothesized that a reduction in extracellular proteolytic activity contributes to the accelerated aging-like phenotype of kl/kl mice. Here we show that PAI-1 deficiency retards the development of senescence and protects organ structure and function while prolonging the lifespan of kl/kl mice. These findings indicate that a SERPIN-regulated cell-nonautonomous proteolytic cascade is a critical determinant of senescence in vivo.
Publisher
National Academy of Sciences,National Acad Sciences
Subject
/ Animals
/ Calcium
/ Cells
/ Cellular Senescence - physiology
/ Cyclin-Dependent Kinase Inhibitor p16 - genetics
/ Cyclin-Dependent Kinase Inhibitor p16 - metabolism
/ Extracellular Space - metabolism
/ Female
/ genes
/ Hemorrhagic Disorders - genetics
/ Hemorrhagic Disorders - metabolism
/ Hemorrhagic Disorders - mortality
/ Kidneys
/ Male
/ Mice
/ Plasminogen Activator Inhibitor 1 - deficiency
/ Plasminogen Activator Inhibitor 1 - genetics
/ Plasminogen Activator Inhibitor 1 - metabolism
/ plasminogen activator inhibitors
/ Proteins
/ Rodents
